Introduction

Amyotrophic lateral sclerosis (ALS) is one of several neurodegenerations affecting the aging nervous system.[1,2] Its pathogenesis is complex and multifactorial and involves the genomics of normal aging, mechanisms that determine selective neuronal vulnerability, the molecular biology of cellular demise,[3,4] and unknown environmental factors.[5] Aging is associated with free radical formation, which injures mitochondrial DNA.[6-8] This effect is more dramatic on irreversibly differentiated cells such as neurons, which have high levels of oxygen utilization. This is the case for corticomotoneurons in the brain and bulbar and spinal motorneurons, which are preferentially, but not exclusively, affected in ALS.[9]

Incidence and prevalence

ALS has a worldwide incidence of about 2 per 100 000 population and a prevalence of 4 per 100 000 population to 7 per 100 000 population. Disease incidence is rising as longevity increases, but there is probably not a genuinely increased incidence of ALS. The age distribution of ALS follows Gompertzian statistics and peaks at between 55 and 65 years of age[10] (Table 1). About 5% to 10% of ALS is hereditary. At present only two abnormal genes have been discovered in ALS. A dismutation of the copper-zinc superoxide-dismutase (CuZn-SOD1) gene occurs in about 20% of hereditary ALS, and thus far about 90 different mutations in this gene have been described.[11,12] Some, such as the D90A and the A4V mutations, have characteristic clinical phenotypes of respectively slow and rapid progression. Transgenic mouse models of the SOD1 mutations have been invaluable in further understanding of the pathogenesis of ALS, and such models have also been fruitful in testing new therapies.[13] Recently another gene, the alsin gene, has been discovered and is associated with young onset and very slowly progressive disease.[14] A host of other genetic mutations are likely responsible for the various clinical phenotypes. For example, the predominance of ALS in males before age 70 years may be related to sex-dependent genes. Protective genes may determine slower rates of ALS progression that occur in about 15% of patients.

Diagnosis

Presently there is no specific biological marker for ALS and the diagnosis depends largely upon the recognition of a characteristic clinical constellation with supportive electrophysiological findings. The recently developed El Escorial criteria classify ALS as suspected, possible, probable, or definite[15] (Table 2). The combination of painless, progressive, but asymmetrical muscle weakness with wasting, fasciculation, and cramps in a multimyotomal distribution, associated with upper motor neuron signs, a normal sensory examination, and normal sphincter and ocular function occurring in a middle-aged patient is almost always due to ALS.

It is necessary to exclude other causes for the symptoms and signs of a cervical cord syndrome such as syringomyelia, arteriovenous malformations, spinal cord tumor, and cervical spondylotic myelopathy. The last disorder can cause a particular dilemma because some degree of degenerative disc disease is common at the age that ALS has its greatest frequency. However, most cases of ALS are readily diagnosed and the error rate of diagnosis in large ALS clinics is less than 10% (Table 3).

Electromyography, which includes conduction studies, needle electromyography, and testing employing transcranial magnetic stimulation of the motor cortex, is very helpful in the confirmation of ALS.[16] Nerve conduction studies help in the diagnosis of other disorders that mimic ALS—such as motor neuropathy with conduction block and Kennedy’s syndrome—but which have a better natural history or are treatable. In ALS needle EMG abnormalities occur frequently in clinically strong limbs with normal muscle bulk. Between 50% to 80% of anterior horn cells can be lost before weakness or muscle wasting occurs. Demonstrating abnormalities in strong muscles helps identify that the disease is widespread. Needle electromyography is also helpful in documenting early diaphragmatic disease, which may be an indication for instituting bimodal positive airway pressure.

Multifocal motor neuropathy with persisting conduction block can only be confirmed using motor conduction studies.[17-19] It closely mimics ALS, affecting patients in the same age range, and has a similar male predominance. The weak or paretic limb is usually of normal muscle bulk, but fasciculations and cramping are frequent. Careful clinical observation confirms that the distribution of the fasciculation is in a peripheral nerve distribution, not in a myotomal distribution as in ALS. Tendon reflexes in the weak limb are usually depressed, whereas in ALS they are typically increased. Using magnetic resonance imaging, thickening of the brachial plexus can be visualized in some cases of motor neuropathy with conduction block.

Kennedy’s disease (spino-bulbar muscular atrophy) also closely resembles ALS.[20] A mutation of the androgen receptor gene linked to chromosome Xq21-22 is specific and leads to an increased number of trinucleotide CAG repeats within the exon 1 coding regions. The number of repeats may correlate with the severity of the phenotype. There are endocrine abnormalities reflecting testicular dysfunction, which include testicular atrophy and gynecomastia, oligospermia or azoospermia, slightly elevated serum gonadotropin levels, glucose intolerance, and feminization of the skin. The clinical characteristics of Kennedy’s disease that clearly distinguish it from other forms of spinal muscular atrophies include X-linked inheritance, a generally older age of symptom onset (older than age 40), diffuse, often marked fasciculations, and involvement of bulbar as well as spinal musculature. The bulbar deficits are lower motor neuron in type. Early puckering of the chin is common. Deep tendon reflexes are frequently depressed or absent, and although sensory complaints are unusual and clinical sensory examination is essentially normal, sensory nerve action potentials are small or absent.[21,22] These abnormalities are considered to be the result of dorsal root ganglion involvement, and postmortem studies have shown histological features of a dying-back process due to disease of the dorsal root ganglia.

Other clinical clues that raise concern that the patient does not have ALS include symmetrical muscle wasting and weakness. Inclusion body myositis or, less frequently, painless polymyositis, are both associated with diffuse muscle weakness with variable wasting occurring most frequently in elderly patients. Chronic inflammatory demylinating polyneuropathy is also often painless and lacks significant sensory abnormalities. Deep tendon reflexes are diffusely absent.

An upper motor neuron deficit is an essential component of ALS. However, it can be subtle and difficult to determine. Several techniques are available that help confirm upper motor neuron involvement. They include functional magnetic resonance imaging, imaging with positron emission tomography,[23] magnetic resonance spectroscopy,[24] and transcranial magnetic stimulation of the motor cortex.[25,26] These techniques have demonstrated that the cortical abnormalities in ALS extend beyond the motor cortex.[27] Various neurophysiologic methods employing transcranial magnetic stimulation indicate early in the course of ALS the motor cortex is hyper-excitable. This is partly related to glutamate toxicity.

Several clinical features, including sensory dysfunction, sphincter impairment, autonomic dysfunction, abnormalities of eye movements, movement disorders, and cognitive dysfunction are considered inconsistent with ALS. However, there are well-documented cases of ALS having one or more of these exceptions. An interesting example is the bladder dysfunction phenotypic of the D90A Cu/Zn SOD1 mutation.[28] Overt clinical dementia can rarely occur in ALS patients. The dementia associated with ALS is typically of the frontal lobe type and different from Alzheimer’s dementia.

The presenting clinical features of ALS are protean and require careful interpretation (Table 4). Some early symptoms may be ignored in elderly and frail patients incorrectly considered to be showing signs of normal aging. Examples include exercise intolerance, a weak voice, decreasing respiratory reserve, walking difficulty, and clumsiness of hand function.

Primary lateral sclerosis predominantly affects the upper motor neuron, presenting with slowly progressive spinobulbar spasticity.[29-31] Histopathology reveals exclusive loss of precentral pyramidal neurons predominantly affecting large pyramidal Betz cells in layer V and secondary pyramidal tract degeneration. Most authorities agree that primary lateral sclerosis represents one end of the spectrum of ALS. This is exemplified by descriptions of classical ALS developing many years after the onset of primary lateral sclerosis.

ALS therapy

Therapy for ALS remains problematic. Numerous clinical trials in ALS have been undertaken over the last decade, but thus far only Rilutek (riluzole), a glutamate antagonist, has been formally approved for its treatment. Recommended dosage is 50 mg twice daily. It is unlikely that a single agent will be developed that is capable of arresting neuronal loss and promoting regeneration. Present strategies are being directed to combining medications.[32] Polytherapy is being investigated with components that include gluatamate antagonists, antioxidants (in particular, those protecting mitochondrial repair systems), anti- apoptotic agents, and anti-inflammatory agents. Inflammatory processes are important in ALS. Even though they may be secondary, they appear key in sustaining the process of cell death.[33] There is a marked increase in mRNA Cox-2 activity in ALS, and trials are presently underway using Celebrex (celecoxib). A specific Cox-2 inhibitor, Celebrex is predominantly used in inflammatory arthropathies.

As with many disorders, patients with ALS do best with a multidisciplinary team approach; symptomatic and supportive measures are imperative. Expertise is required in respiratory function, nutrition, rehabilitative and occupational measures (to improve quality of life), and social work and counseling—especially regarding end-of-life decisions. Use of bimodal positive airway pressure, which actively assists the inspiratory phase of respiration, is rapidly becoming standard care for ALS patients in North America. Most patients quickly learn to use the device confidently. Enteral nutrition delivered via a percutaneous endoscopically placed gastrostomy is also now commonplace. Early implementation is important. Excessive salivation is a frequent problem in ALS and can be alleviated by use of a scopolamine transdermal patch. If this fails, small doses of radiation to the submandibular glands are frequently successful. A home suction machine is usually required when excess salivation is more persistent. Thickened mucus is a less frequent problem and can be managed by use of a mucolytic agent such as Mucomyst (acetylcysteine).

Conclusion

Over the last decade awareness of ALS has significantly increased, diagnosis is being achieved in a more timely fashion, and overall care is better. Nevertheless a real therapeutic agent remains elusive. Better drug delivery, unraveling the ALS genome, and the application of pharmacogenomics and stem cell therapy are some future avenues that are likely to bring success.

Competing Interests

None declared.

 Table 2. El Escorial criteria for ALS.

 Table 3. Incorrect diagnosis in 1113 patients with ALS.

 Table 4. Presenting complaints in 1113 patients with ALS.

Andrew Eisen MD, FRCPC

Dr Eisen is professor emeritus, Division of Neurology, University of British Columbia.